EP0941218A1 - Antithrombotic organic nitrates - Google Patents
Antithrombotic organic nitratesInfo
- Publication number
- EP0941218A1 EP0941218A1 EP97951890A EP97951890A EP0941218A1 EP 0941218 A1 EP0941218 A1 EP 0941218A1 EP 97951890 A EP97951890 A EP 97951890A EP 97951890 A EP97951890 A EP 97951890A EP 0941218 A1 EP0941218 A1 EP 0941218A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- chosen
- integer
- carbon atoms
- groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003146 anticoagulant agent Substances 0.000 title claims abstract description 8
- 230000002785 anti-thrombosis Effects 0.000 title abstract description 9
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 title description 2
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- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims abstract description 16
- 229960004605 timolol Drugs 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- -1 Moveltilpril Chemical compound 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229960004676 antithrombotic agent Drugs 0.000 claims description 3
- 229960002680 enalaprilat Drugs 0.000 claims description 3
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- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000005717 substituted cycloalkylene group Chemical group 0.000 claims description 3
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- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 claims description 2
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 claims description 2
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- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 claims description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims description 2
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 claims description 2
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- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims description 2
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000330 bupranolol Drugs 0.000 claims description 2
- 229960000830 captopril Drugs 0.000 claims description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 2
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 claims description 2
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- 229960005227 delapril Drugs 0.000 claims description 2
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 claims description 2
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- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229960001195 imidapril Drugs 0.000 claims description 2
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 claims description 2
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- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 claims description 2
- 229960000831 levobunolol Drugs 0.000 claims description 2
- 229960002394 lisinopril Drugs 0.000 claims description 2
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 claims description 2
- 229960003134 mepindolol Drugs 0.000 claims description 2
- 229960002704 metipranolol Drugs 0.000 claims description 2
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 claims description 2
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- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 claims description 2
- 229960001455 quinapril Drugs 0.000 claims description 2
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 claims description 2
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims description 2
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- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 claims description 2
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- 239000002220 antihypertensive agent Substances 0.000 claims 1
- 229940045200 cardioprotective agent Drugs 0.000 claims 1
- 239000012659 cardioprotective agent Substances 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 230000002526 effect on cardiovascular system Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 34
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- 239000000243 solution Substances 0.000 description 20
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- 238000000034 method Methods 0.000 description 14
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- 238000006243 chemical reaction Methods 0.000 description 12
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- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 8
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- ZETOHPSSBWBMED-UHFFFAOYSA-N 4-nitrooxybutanoic acid Chemical compound OC(=O)CCCO[N+]([O-])=O ZETOHPSSBWBMED-UHFFFAOYSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102100021587 Embryonic testis differentiation protein homolog A Human genes 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000898120 Homo sapiens Embryonic testis differentiation protein homolog A Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- FTOAOBMCPZCFFF-UHFFFAOYSA-N barbitone sodium Natural products CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- ATADHKWKHYVBTJ-UHFFFAOYSA-N hydron;4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCC(O)C1=CC=C(O)C(O)=C1 ATADHKWKHYVBTJ-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RGHFKWPGWBFQLN-UHFFFAOYSA-M sodium;5,5-diethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC1(CC)C([O-])=NC(=O)NC1=O RGHFKWPGWBFQLN-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to new products having an antithrombotic activity.
- Cyclooxygenase (COX) -inhibiting anti-inflammatory products are known from previous patent applications in the name of the Applicant. See in particular the published patent applications WO 94/04484, WO 94/12463, WO 95/09831, WO95/30641. These patent applications referred to non-steroid anti -inflammatory products with a non-acid ending and to those with an acid ending mentioned as products known in the art .
- Said products showed a much lower toxicity level compared to the reference products not containing group -ON0 2 .
- the products of the invention as defined below are effective in inhibiting platelet aggregation induced by different kinds of stimuli, in particular collagen and thrombin, and at the same time exhibit high safety in general, in particular a high gastric safety, without causing lesions to the gastrointestinal mucosa in the treated animals.
- a subject of the present invention are the compounds, or their compositions, of the general formula:
- R Ia , R IIa , n Ia are as defined in la;
- N 3 is H, (CH 3 ) 2 CH-CH-OCOCH 2 CH 3 , or a free valence to which X ⁇ binds (that is, N 3 is absent) ;
- R Ib is chosen from:
- N 2 is as above defined, where at least one of the groups N 3 or N 2 has a free valence capable of binding to X (when it is
- Rg ⁇ is chosen fr ⁇ r ⁇ :
- X- j _ is a bivalent connecting bridge chosen from the following: YO where Y is a linear or whenever possible branched C 1 -C 20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; Y- j _ chosen from
- n 3 is an integer from 0 to 3 ;
- nf is an integer from 1 to 6 , preferably from 2 to 4;
- R lf H, CH 3 and nf is an integer from 1 to 6; preferably from 2 to 4.
- connection between A and X 1 is, as seen, of an ester or amide type (NH or NR lc , as defined in X) . Any synthetic route well known for forming these bonds can be used.
- the most direct synthetic route includes reaction of acyl chlorides A-C0-C1, or A-(C0-C1) 2 , in halogen alcohols of the type HO-Y a -Cl, HO-Y a -Br,- HO-Y a -I, where Y a is equal to Y or Y- ⁇ as above defined without the oxygen atom ⁇ 0- , in experimental conditions which are part of the known art .
- reaction products of formula A-CO-0-Y a -Cl (Br, I) can also be obtained by reacting the sodium or potassium salts of said acids A-CO-OH with di-halogen derivatives of the general formula Y a Cl 2 , Y a Br 2 or Y a I 2 .
- reaction products are converted into the final pro- ducts by reaction with AgN0 3 in acetonitrile according to processes known in the prior art.
- the synthetic sequence includes reaction of the same acyl chlorides A-CO-Cl with amino alcohols of the general formula NH 2 -Y a -OH or NHR lc -Y a -OH to give amides of the general formula: A-CO-NH-Y a -OH or A-CO-NR lc -Y a -OH in accordance with known methods.
- the sequence may be represented as follows:
- Example 1 A general method for the -OH group is described in Example 1 only for illustrative purposes.
- the products of the invention as described above are novel as medicaments in general .
- they are no- vel for their antithrombotic activity and are also novel as compounds as such.
- Additional pharmaceutical uses which can be mentioned for the products of the invention are, for example, their antihypertensive activity (e.g. arterial hypertension, glaucoma) and their cardioprotective activity (e.g. angina pe- ctoris, cardiac failure, coronary ischaemia) .
- their antihypertensive activity e.g. arterial hypertension, glaucoma
- their cardioprotective activity e.g. angina pe- ctoris, cardiac failure, coronary ischaemia
- the products of the invention showed an extremely satisfactory pharmaco-therapeutic profile with improved efficacy compared to the precursors which do not contain group -0N0 2 and, at the same time, showed superior safety.
- the products of the invention exhibit an antihypertensive activity combined with an antithrombotic activity. This is an outstanding benefit in the treatment of cardiovascular disease in general since the purpose of any therapeutical approach is to ensure to the patient an altogether reduced risk of cardiovascular disease, such as myocardial or cerebral infarction and atherosclerosis (Goodman & Gilman "The pharmacological basis of therapeutics", Ed . J. Hardman, L. Limbrid, pages 747, 1354-7, 1996) .
- the starting point is timolol maleate (a commercial product) , the timolol having the general formula
- Timolol maleate (2.0 g) was treated with a solution of 10% NaOH (30 ml) . 30 ml of CH 2 C1 2 were added and ' then the phases were separated. The aqueous phase was extracted several times with CH 2 C1 2 . The pooled organic phases were dried (Na 2 S0 4 ) and the solvent evaporated at reduced pressure. 1.4 g of pure product were obtained (yield 96%) .
- NO-ENA enalaoril
- DMF dimechylfarmacni.de
- TAA triethylamine
- the experimental groups were made up of 6 to 8 samples to allow appropriate statistical evaluation, which was carried out when needed.
- Collagen (type 6, Sigma) was then administered intravenously at a dose of 2 mg/kg.
- Three minutes later two blood samples (A and B) were colle- cted from the carotid artery using 2.5-ml plastic syringes in the following manner: sample A, 0.4 ml of blood in 1.6 ml of EDTA/formalin buffer (ETDA tetrasodium salt 24 mM, KH 2 P0 4 1.3 mM, Na 2 P0 4 13.4 mM) , the samples were then transferred into 5-ml polystyrene test tubes and allowed to settle for 15 minutes at ambient temperature. After this time, the platelet aggregations in sample A were fixed in formalin, while those from sample B were treated with EDTA.
- Platelet count was then made in each sample using a conventional microscope.
- the count for sample B was the total number of platelets, while for sample A were considered only non-aggregated platelets.
- the results were expressed as per-cent aggregation, calculated as follows: [1- (platelet count in sample A) / (platelet count in sample B) ] x 100 ⁇ .
- the results were expressed as per-cent inhibition of the control group (vehicle) and shown in Table 1.
- NO-ENA The ability of NO-ENA to inhibit hypertension was evaluated using an in vivo model as described by Ribeiro et al . (Hypertension 20, 298, 1992). 5 groups of male Wistar rats (235 to 284 g) received a daily intravenous dose of 10 mg/kg of, respectively, NO-ENA, enalapril, NO-TIM, timolol or vehicle for 5 days. Arterial hypertension was induced by administration of N w -nitro-L-argininemethyl ester (L-NAME) in the drinking water for 6 weeks . L-NAME was dissolved in the drinking water at a concentration of 60 to 70 mg 100 ml so as to administer a daily amount of about 60 mg kg -1 . One hour after treatment the systemic blood pressure- was raeasu- red by the tail-cap method (Zats, Lab. Anim. Sci.42, 198,
- EXAMPLE 3B STUDY OF OCULAR HYPOTENSIVE ACTIVITY AND OCULAR SAFETY OF NO-ENA OR NO-TIM VERSUS ENALAPRIL OR TIMOLOL IN RABBITS
- EXAMPLE 3E STUDY OF NO-ENA EFFECTS ON INDUCED BRONCHOCON- STRICTION IN GUINEA PIGS VERSUS ENALAPRIL
- Bronchoconstriction induced by capsaicin in Guinea pigs is an animal model related to the ability of ACE (angioten- sin-converting enzyme) inhibitors to cause cough in patients (Subissi et al . , J. Cardiovasc . Pharmacol .20/1, 139-146, 1992) .
- ACE angioten- sin-converting enzyme
- Adopted test conditions were as previously described by Del Soldato et al.(J. Pharmacological Methods 5, 279, 1981).
- Female Guinea pigs weighing 300 to 400 g were anaesthetised by intraperitoneal injection of sodium 5 , 5-diethylbarbitu- rate (200 mg/kg) and maintained under artificial respiration at constant positive pressure.
- the right jugular vein was incannulated for administering test compound.
- the other end of the can- nula was connected to a syringe for intraduodenal administration of NO-ENA (10 mg/kg) , enalapril (10 mg/kg) or vehicle. 45 minutes later, 0.1 ml of capsaicin (1 ⁇ g/kg) was injected into the jugular vein of the animals. Before and after injection of capsaicin, changes in the tidal area were measured by a modified Konzett apparatus connected to a suitable polygraphic amplifier (Hewlett Packard) .
- the nitroderivatives which are an object of the present invention show marked antithrombotic and cardiovascular activity with excellent safety when compared to reference products.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI9730450T SI0941218T1 (en) | 1996-11-14 | 1997-11-12 | Antithrombotic organic nitrates |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT96MI002368A IT1295694B1 (en) | 1996-11-14 | 1996-11-14 | NITROXIS DERIVATIVES FOR THE PREPARATION OF MEDICATIONS WITH ANTI-THROMBINIC ACTIVITY |
ITMI962368 | 1996-11-14 | ||
PCT/EP1997/006311 WO1998021193A1 (en) | 1996-11-14 | 1997-11-12 | Antithrombotic organic nitrates |
Publications (2)
Publication Number | Publication Date |
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EP0941218A1 true EP0941218A1 (en) | 1999-09-15 |
EP0941218B1 EP0941218B1 (en) | 2002-10-16 |
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Application Number | Title | Priority Date | Filing Date |
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EP97951890A Expired - Lifetime EP0941218B1 (en) | 1996-11-14 | 1997-11-12 | Antithrombotic organic nitrates |
Country Status (18)
Country | Link |
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US (1) | US6242432B1 (en) |
EP (1) | EP0941218B1 (en) |
JP (1) | JP4264137B2 (en) |
KR (1) | KR100504122B1 (en) |
CN (1) | CN1094931C (en) |
AT (1) | ATE226199T1 (en) |
AU (1) | AU729423B2 (en) |
BR (1) | BR9712959B1 (en) |
CA (1) | CA2272063C (en) |
DE (1) | DE69716461T2 (en) |
DK (1) | DK0941218T3 (en) |
ES (1) | ES2186013T3 (en) |
HU (1) | HUP0000667A3 (en) |
IL (1) | IL129768A (en) |
IT (1) | IT1295694B1 (en) |
PT (1) | PT941218E (en) |
RU (1) | RU2190594C2 (en) |
WO (1) | WO1998021193A1 (en) |
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IT1256345B (en) | 1992-08-20 | 1995-12-01 | NITRIC ESTERS OF PHENYLACETIC 2- (2,6-DI-HALO-PHENYLAMIN) DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION | |
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WO1997031896A1 (en) * | 1996-03-01 | 1997-09-04 | Sankyo Company, Limited | Thiazolidine derivatives |
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WO1998021193A1 (en) | 1998-05-22 |
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CN1242768A (en) | 2000-01-26 |
JP2001507676A (en) | 2001-06-12 |
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KR20000053251A (en) | 2000-08-25 |
DE69716461T2 (en) | 2003-06-26 |
ATE226199T1 (en) | 2002-11-15 |
IL129768A (en) | 2004-02-19 |
ES2186013T3 (en) | 2003-05-01 |
IT1295694B1 (en) | 1999-05-27 |
PT941218E (en) | 2003-03-31 |
AU729423B2 (en) | 2001-02-01 |
ITMI962368A1 (en) | 1998-05-14 |
BR9712959A (en) | 2000-02-01 |
HUP0000667A3 (en) | 2000-08-28 |
CA2272063A1 (en) | 1998-05-22 |
EP0941218B1 (en) | 2002-10-16 |
HUP0000667A2 (en) | 2000-07-28 |
BR9712959B1 (en) | 2010-06-01 |
RU2190594C2 (en) | 2002-10-10 |
CA2272063C (en) | 2008-05-27 |
US6242432B1 (en) | 2001-06-05 |
KR100504122B1 (en) | 2005-07-27 |
AU5551998A (en) | 1998-06-03 |
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